1. Field of the Invention
The present invention relates to the field of pharmaceutical formulations of anti-fungal drugs. More specifically, the present invention relates to novel formulations of itraconazole.
2. Description of the Related Art
Itraconazole (C35H38Cl28O4) marketed as Sporanox®, a registered trademark of Janssen Pharmaceuticals, an itraconazole formulation comprising hydroxylpropyl-b-cyclodextrin, is a triazole antifugal agent effective against three main groups of fungi: histoplasmosis, aspergillosis, and blastomycosis (1-2). All three types of fungi can cause serious damage to the lungs, heart, and other major organs if not treated or treated unsuccessfully.
The goal of antifungal therapy is to stop the spread of pathogens while they are still isolated to a single organ. When itraconazole is injected, the standard initial dose is 200 milligrams infused over the course of an hour. Another dose on the first day and single doses on each of the next five to ten days is usually sufficient to cure an infection.
Itraconazole has been used for the treatment of both systemic fungal infection and superficial mycoses (3-4), and also been successfully used in the treatment of severe necrotizing pneumonias, invasive pulmonary aspergillosis (5-6).
Itraconazole is a weakly basic compound (pKa=3.7) of high lipophilicity with a n-octanol/water partition coefficient of log Po/w=5.66 at pH=8.1 (7-8). The drug has very poor water solubility of about 1 ng/mL at neutral pH and approximately 4 mcg/mL at pH=1 (9). Sporanox® I.V. was the only commercially available intravenous formulation of itraconazole to achieve practically applicable solubilization of the drug by hydroxylpropyl-β-cyclodextrin (HP-β-CD) complexation (Janssen Pharmaceuticals). However, sales and distribution of Sporanox® I.V. Injection in the United States was discontinued because of renal toxicity caused by its excipient, hydroxylpropyl-β-cyclodextrin. According to the package insert, each milliliter of Sporanox® I.V. contains 10 mg of itraconazole solubilzed by 400 mg of hydroxylpropyl-β-cyclodextrin as a solubilizing complex. Following intravenous administration, there was reportedly a 6-fold reduced clearance of hydroxylpropyl-β-cyclodextrin in renal impaired patients. Studies also have shown that hydroxylpropyl-β-cyclodextrin produced pancreatic adenocarcinomas in a rat carcinogenicity study.
The development of alternate clinically applicable intravenous formulations of itraconazole is difficult mainly due to its poor water solubility. Various pharmaceutically acceptable solvents have been tested for potential parenteral formulations of itraconazole (10). However, when these formulations were diluted with water, itraconazole precipitated in aqueous solution over the course of time. Thus, these formulations are not suitable for use as injections.
Several other approaches have been used in the prior art to overcome the non-solubilizing problems in an effort to find a way of delivering itraconazole intravenously. Rhee et al (11) reported an o/w microemulsion formulation of itraconazole containing benzyl alcohol and medium chain triglyceride as the oil phase. A self-emulsifying formulation of itraconazole for improved oral bioavailability has been reported (12). But microemulsions have limited water capacity and often have potential of drug precipitation at high aqueous content. A binary lipid nanoparticle formulation of itraconazole was recently developed (13) for parenteral administration of itraconazole. The nanoparticle has mean particle sizes of 190-240 nm containing triolein as the lipid core and tristearin as the solid core, alone with PEGylated phospholipid as stabilizer. Nanoparticle is a promising dosage formulation (14), but there were many practical problems to be addressed such as dosage form uniformity, macrophage endocytosis, etc. before clinical application becomes reality. Finally, a mixed polymer micellar formulation (15) was introduced using a mixed polymers including mPEG-PLA, PLA-COOH and PLA-COONa. However, actual applicability of such formulation needs further investigation.
There is, therefore, a need for improved itraconazole parenteral formulations in solvent systems that are capable of solubilizing itraconazole when diluted in an aqueous medium for intravenous administration. The present invention fulfils this longstanding need in the art.